Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.

Cell Death and Proliferation Institute of Biomedical Research of Barcelona Instituto de Salud Carlos 3 Madrid 28029 Spain; USC Research Center for ALPD Keck School of Medicine Los Angeles United States CA 90033

Center for Regenerative Medicine Institute for Regenerative and Repair The University of Edinburgh Edinburgh UK EH16 4UU; School of Engineering Institute for Bioengineering The University of Edinburgh Faraday Building Colin Maclaurin Road EH9 3 DW Scotland UK

Center for Regenerative Medicine Institute for Regenerative and Repair The University of Edinburgh Edinburgh UK EH16 4UU; School of Engineering Institute for Bioengineering The University of Edinburgh Faraday Building Colin Maclaurin Road EH9 3 DW Scotland UK; Institute of Biological Chemistry Biophysics and Bioengineering Heriot Watt University Edinburgh EH12 2AS Scotland UK

Center for Toxicogenomics and Human Health Genetics Oncology and Human Toxicology NOVA Medical School Faculty of Medical Sciences Universidade NOVA de Lisboa Lisbon Portugal

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas 28007 Madrid Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Derio Bizkaia 48160 Spain; IKERBASQUE Basque Foundation for Science Bilbao Bizkaia 48015 Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Instituto de Salud Carlos 3 Madrid 28029 Spain; Servicio de Farmacología Clínica Instituto de Investigación Biomédica de Málaga IBIMA Hospital Universitario Virgen de la Victoria UICEC SCReN Universidad de Málaga Málaga Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Instituto de Salud Carlos 3 Madrid 28029 Spain; Unidad de Gestión Clínica de Enfermedades Digestivas Instituto de Investigación Biomédica de Málaga IBIMA Hospital Universitario Virgen de la Victoria Universidad de Málaga Malaga Spain

Department of Immunology Ophthalmology and ENT Complutense University School of Medicine 28040 Madrid Spain; Health Research Institute Gregorio Marañón 28007 Madrid Spain

Department of Molecular Biology and Genetics Faculty of Science Bilkent University Ankara Turkey; Interdisciplinary Neuroscience Program Bilkent University Ankara Turkey; UNAM Institute of Materials Science and Nanotechnology Bilkent University Ankara Turkey

Department of Optical and Biophysical Systems Institute of Physics of the Czech Academy of Sciences Prague Czech Republic

Exosomes Laboratory Center for Cooperative Research in Biosciences Derio Bizkaia 48160 Spain

INSERM Univ Rennes INRAE Institut NUMECAN UMR_A 1341 UMR_S 1241 F 35000 Rennes France

Institute for Bioengineering School of Engineering The University of Edinburgh Edinburgh EH8 3DW UK

Instituto Investigaciones Biomédicas August Pi i Sunyer Instituto de Salud Carlos 3 Madrid 28029 Spain

National Institute for Health Research Nottingham Biomedical Research Centre Nottingham University Hospital NHS Trust and University of Nottingham Nottingham UK

Research Institute for iMedicines Faculty of Pharmacy Universidade de Lisboa 1649 003 Lisbon Portugal

University of Oslo and the Oslo University Hospital Oslo Norway; Hybrid Technology Hub Center of Excellence Institute of Basic Medical Sciences University of Oslo Oslo Norway; Department of Pediatric Research Oslo University Hosptial Oslo Norway

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